Copper-Catalyzed Oxidations with

Marko and coworkers [109, 110] showed that a combination of CuCl (5 mol%), phenanthroline (5 mol%), and di-tert-butylazodicarboxylate, DEAD (5 mol%), in the presence of 2 equivalents of K2CO3, catalyzes the aerobic oxidation of allylic and 

The nature of the copper counterion vas critical, with chloride, acetate and triflate proving to be the most effective. Polar solvents such as acetonitrile inhibit the reaction, whereas smooth oxidation takes place in apolar solvents such as toluene. An advantage of the system is that it tolerates a variety of functional groups (see Table 5.10 for examples). Serious drawbacks of the system are the low activity, the need for two equivalents of K2CO3 (relative to substrate), and the expensive DEAD as a cocatalyst. According to a later report [111] the amount of K2CO3 can be reduced to 0.25 equivalents by changing the solvent to fluorobenzene. 

Semmelhack ef al. [112] reported that the combination of CuCl and 4-hydroxy TEM PO catalyzes the aerobic oxidation of alcohols. However, the scope was limited to active benzylic and allylic alcohols, and activities were low (10mol% of catalyst was needed for smooth reaction). They proposed that the copper catalyzes the reoxidation 

We have shown, in stoichiometric experiments, that reaction of copper(I) with TEMPO affords a piperidinyloxyl copper(II) complex. Reaction of the latter with a molecule of alcohol afforded the alkoxycopper(II) complex and TEMPOH. Reaction of the alkoxycopper(II) complex with a second molecule of TEMPO gave the carbonyl compound, copper(I), and TEMPOH. This mechanism resembles that proposed for the aerobic oxidation of alcohols catalyzed by the copper-dependent enzyme, galactose oxidase, and mimics thereof. Finally, TEMPOH is reoxidized to TEMPO by oxygen. We have also shown that copper in combination with PIPO affords an active and recyclable catalyst for alcohol oxidation [18]. 

In addition, many variations of the Cu/Tempo system have been published. In a first example, Knochel et al. [114] showed that CuBr.Me2S with perfiuoroalkyl-substituted bipyridine as the ligand was capable of oxidizing a large variety of primary and secondary alcohols in a fiuorous biphasic system of chlorobenzene and perfluorooctane (see Eq. (5.14)). In the second example Ansari and Gree [115] showed that the combination of CuCl and TEM PO can be used as a catalyst in 1 -butyl-3-methylimidazolium hexafluorophosphate, an ionic liquid, as the solvent. However, 

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More recently, Jin et al. discovered an efficient copper-catalyzed cyanation of arenes 119 nsing benzyl nitrile as a cyanide anion surrogate, which fiunishes aromatic nitriles 120 (Scheme 5.84) [85]. The process involves at least three steps, where (1) benzyl nitrile undergoes a copper-catalyzed oxidation with air to generate A and B, accompanied by the generation of Cu(II) species (2) cyanide anion is formed throngh a retro-cyanohydrination of A or/and hydrolysis of B and (3) the in situ-generated cyanide anion participates in the copper(II)-catalyzed aerobic oxidative C—H fnnctionalization to afford the cyanation product. 

The main product of the Elbs reaction is the 1,4-dihydroxybenzene (hydro-quinone). If the para position is already occupied by a substituent, the reaction occurs at an ortho position, leading to a catechol derivative although the yields are not as good as for a hydroquinone. Better yields of catechols 7 can be obtained by a copper-catalyzed oxidation of phenols with molecular oxygen ... 

Scheme 3 Proposed catalytic mechanism for the copper catalyzed oxidation of alcohols with TEMPO as oxidant...

Oxidation of Cu with O2 is markedly slower than the analogous oxidation by TEMPO. The existence of a copper-centered dehydrogenation step was supported by investigating kinetic isotope effects and Hammett correlation studies using different substituted benzyhc alcohols. The /1-hydrogen abstraction was postulated to occur in a concerted mechanism with an -coordinated TEMPO radical bgand (Scheme 4). As such, this TEMPO-mediated copper-catalyzed oxidation of alcohols bears resemblance... 

The proposed mechanism agrees completely with that suggested by Allen for the copper-catalyzed oxidation of oxalate by peroxydisulfate (2). 

The utility of the method was demonstrated with a variety of electron-rich and electron-poor aryl aldehydes, but the method was not suitable for aliphatic aldehydes. No racemization was observed in the copper-catalyzed oxidative amidation reaction when an optically active amine, (S)-valine methyl ester, was employed. 

Propylene oxide is one of the raw materials used to manufacture rubbery and crystalline polyepoxides. R. J. Herold and R. A. Livigni describe propylene oxide polymerization with hexacyanometalate salt complexes as catalyst. Polyphenylene oxide is made by copper catalyzed oxidative coupling of 2,6-dimethylphenol. G. D. Cooper, J. G. Bennett, and A. Factor discuss the preparation of copolymers of PPO by oxidative coupling of dimethylphenol with methylphenylphenol and with diphenylphenol. 

Ghyczy M, Boros M (2001) Electrophilic methyl groups present in the diet ameliorate pathological states induced by reductive and oxidative stress a hypothesis. Br J Nutr 85 409-414 Gilbert BC, Silvester S (1997) EPR studies of the role of copper in bio-organic free radical reactions. Copper-catalyzed oxidations of thiols with peroxides, especially those involving glutathione. Nukleonika 42 307-322... 

The Wacker Oxidation is an industrial process, which allows the synthesis of ethanal from ethene by palladium-catalyzed oxidation with oxygen. Copper serves as redox cocatalyst. 

Mechanism of the copper-catalyzed reactions with low-valent organometallic reagents and co-oxidant... 

In products with complex combinations of various types of flavonoids and other phenolic compounds, effort has been made to ascribe the antioxidant activity of the product to different classes of polyphenols. Frankel et al. (1995) studied 20 selected California wines and related the antioxidant activity to the polyphenolic components of the wines, rather than to resveratrol. Antioxidant activity was measured by the ability of the wines to inhibit copper-catalyzed oxidation of human LDL. The correlation coefficient between antioxidant activity and total phenolic components of the wines was r = 0.94. Individual phenolic compounds (gallic acid, catechin, myricetin, quercetin, caffeic acid, rutin, epicatechin, cyanidin, malvidin-3-glucoside) contributed to the antioxidant activity. The correlation coefficient for the compounds ranged from r = 0.92 to r = 0.38 in descending order. 

The antioxidant activities of red and white commercial grape juices have been studied using in vitro inhibition of the copper-catalyzed oxidation of human LDL (Frankel et al., 1998). The correlation between total phenols, expressed as GAE, and relative percent of inhibition of LDL oxidation was r = 0.99. In red Concord grape juices, the antioxidant activity was related to the anthocyanin levels. In the white grape juice, the antioxidant activity was associated with the levels of hydrox-ycinnamates (caffeic acid) and flavanols (catechin). When compared at the same level of total phenolics (10 pM GAE), the antioxidant activities of the grape juices were comparable to the antioxidant activities of red wine (Frankel et al., 1995). Laplaud et al. (1997) found protective action of copper-mediated LDL oxidation in aqueous V. myrtillus extracts. On a molar base, the extracts were more efficient than ascorbic acid and BHT in inhibiting LDL oxidation. 

A new method, recently developed at DuPont [81], is based on the copper-catalyzed oxidative fluorination of aromatic compounds with hydrofluoric acid in the presence of oxygen (Scheme 2.31). 

Scheme 5 Copper-catalyzed oxidative alkylation of tertiary amines with malonates...

Scheme 11 Copper-catalyzed oxidative coupling of indoles with tetrahydroisoquinolines...

Scheme 18 Copper-catalyzed oxidative alkynylation of aliphatic tertiary amines with terminal...

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